We propose a 5-year competitive renewal to extend our studies of the families of bipolar, hospitalized and ambulatory depressed, and normal probands which began in 1976. The long-term goal of this study, which was conducted collaboratively between Yale Departments of Psychiatry, Epidemiology and Human Genetics, and the NIMH Psychogenetics Unit, is to gain better understanding of family-genetic factors in depressive disorders through the use of the techniques of epidemiology and genetics. Because diagnostic heterogeneity ia a major problem in family aggregation studies, we have focused substantial efforts on defining possible homogeneous subgroups. We have identified two subtypes of depressive disorders in probands, which have increased morbidity of major depression in relatives and suggest specificity in transmission. These are probands with early onset major depression (less than 30 years), and probands with major depression plus panic disorder. We are requesting a renewal to validate and study these subtypes more intensively. In the proposed continuation we will: 1) Obtain new samples of probands with early onset (less than 30 years) major depression and of probands with panic disorders with and without major depression; 2) Collect detailed information on their extended pedigrees which include children ages 6-17 of the above proband groups, as well as first and second degree relatives; and 3) Conduct genetic linkage studies on selected informative families from the above groups using newer recombinant DNA techniques, and continue to develop genetic models appropriate for psychiatric traits. The NIMH collaborators will conduct similar studies in the families of early onset bipolar probands. Focusing on these groups, which are promising in terms of homogeneity and increased transmission in relatives, and exploiting new techniques and findings from epidemiology, and statistical and molecular genetics, will better enable us to accomplish the goal of this study of gaining an understanding of the etiology of the affective disorders.